Ion channels are proteins that span the lipid bilayer of the cell membrane and provide an aqueous pathway through which specific ions such as Na+, K+, Ca2+ and Cl− can pass (Herbert, 1998). Potassium channels represent the largest and most diverse sub-group of ion channels and they play a central role in regulating the membrane potential and controlling cellular excitability (Armstrong & Hille, 1998). Potassium channels have been categorized into gene families based on their amino acid sequence and their biophysical properties (for nomenclature see Gutman et al., 2003).
Compounds which modulate potassium channels have multiple therapeutic applications in several disease areas including autoimmune, inflammatory, cardiovascular, neuronal, auditory, renal and metabolic mediated diseases (Shieh et al., 2000; Ford et al., 2002, Xie et al, 2004, Cahalan et al, 1997). The potassium channel Kv1.3 is found in a number of tissues including neurons, blood cells, osteoclasts, macrophages, epithelia, and T- and B-lymphocytes. Furthermore, Kv1.3 inhibition has been shown to modulate T-cell function which has implications in many autoimmune diseases including psoriasis, rheumatoid arthritis, multiple sclerosis, obesity, diabetes and inflammatory bowel disease (Beeton et al., 2006).
Kv1.3 Channel Blockers for Autoimmune Disorders
The role of autoreactive, late-stage, memory T-cells in the pathogenesis of a variety of autoimmune diseases including psoriasis, rheumatoid arthritis, multiple sclerosis, IBD and others is well established. Activation of TEM cells is followed by substantial up-regulation of Kv1.3 channel expression and, as a result, Kv1.3 becomes the predominant route of potassium efflux from the cell. Thus, selective blockade of Kv1.3 causes membrane depolarisation and inhibition of Ca2+ influx, leading to inhibition of cytokine production and cell proliferation and function. Kv1.3 thus represents a novel therapeutic target of great interest for autoimmune disease control.
T-cells and Autoimmunity
T-cells are lymphocytes which play a central role in cell mediated immunity. One of the major forms of T-cell is the helper T-cell (TH), also known as CD4+ cells which plays an essential role in the development of autoimmune diseases. Through the production of the cytokine interleukin 2 (IL-2), CD4+ T-cells can create the second main type of T-cell known as cytotoxic T-cells (CD8+). Naïve (inactive) CD4+ and CD8+ T-cells express both proteins (CCR7+CD45RA+) and use the chemokine receptor CCR7 as a key to gain entry into lymph nodes. Within lymph nodes, the naïve T-cells encounter antigen and through an activation process, change into “effector” T-cells that produce cytokines and proliferate. Once the ensuing immune response subsides, most naïve effectors die, but a few differentiate into long-lived central memory cells (TCM). TCM cells, like naïve cells, use CCR7 to home to the lymph nodes to encounter their cognate antigen. Upon antigenic stimulation, TCM cells change into “TCM effector” cells that produce cytokines and proliferate. They too suffer the same fate as naïve effectors, the majority dying after the immune response wanes, leaving a few long-lived survivors for further challenge. Repeated antigenic challenge, as might happen in autoimmune diseases or in chronic infections, causes TCM cells to differentiate into short-lived “effector memory T-cells” (TEM) that lack expression of both CCR7 and CD45RA, and do not need to home to lymph nodes for antigen-induced activation. A subset of CD8+ TEM cells reacquire CD45RA and become CCR7−CD45RA+ TEMRA cells. Upon activation, both CD4+ and CD8+ TEM cells change into TEM effectors that migrate rapidly to sites of inflammation and produce large amounts of the proinflammatory cytokines, interferon-γ (IFN-γ) and tumor necrosis factor α (TNFα). In addition, CD8+ TEM effectors carry large amounts of perforin and are therefore immensely destructive (Wulff et al, 2003, Beeton et al, 2005).
Functional Role of Kv1.3 in T-cells and Autoimmune Disorders
Human T-cells express two K+ channels, Kv1.3 and IKCal, that provide the counterbalance cation efflux necessary for the sustained elevation of cytosolic Ca2+ levels required for gene transcription, proliferation and cytokine secretion (Panyi et al, 2004, Chandy et al, 2004). The Kv1.3 and IKCal (also known as KCa3.1) channels regulate membrane potential and facilitate Ca2+ signalling in T-lymphocytes. Kv1.3 opens in response to membrane depolarisation and maintains the resting membrane potential (initiation phase), whereas IKCal opens in response to an increase in cytosolic Ca2+ and hyperpolarises the membrane potential (Beeton et al, 2001). Selective blockade of K+ channels leads to membrane depolarisation, which in turn inhibits Ca2+ influx and shuts down cytokine production and cell proliferation. Early in vitro studies, using channel blocker toxins, clearly demonstrate that Kv1.3 channels are essential for the synthesis (gene activation) and secretion of the cytokine IL-2 after T-cell activation (Price et al, 1989) and provide a rationale for the potential therapeutic use of inhibitors of this channel in immunological disorders. The role of autoreactive T-cells in the pathogenesis of autoimmune diseases has clearly been demonstrated in animal models. Disease-specific, autoreactive T-cells in several other autoimmune diseases are also reported to exhibit a memory phenotype. Autoreactive TEM cells are also implicated in psoriasis, rheumatoid arthritis, multiple sclerosis, IBD, vitiligo, uveitis, pemphigus, inflammatory myopathies, Hashimito disease, and scleroderma (Beeton et al, 2005). “Late” memory T- and B-cells have been implicated in the disease progression and tissue damage in a number of autoimmune diseases, in transplant rejection and chronic graft-versus-host disease. Modulators of the Kv1.3 channel may allow selective targeting of disease-inducing effector memory T-cells and memory B-cells without compromising the normal immune response and as a result are likely to have a preferred side-affect profile than agents that bring about more general immunosuppression.
The observation that the Kv1.3 blocker margatoxin (MgTX) effectively suppressed the delayed-type hypersensitivity (DTH) response in vivo was provided by Koo et al, 1999. In addition MgTX was also shown to inhibit primary antibody response in non-sensitised animals (secondary antibody response was not affected by MgTX. These latter results are in agreement with the notion that Kv1.3 channels are predominant in resting T lymphocytes and regulate their function, while IKCal channels are more important in pre-activated T lymphocytes. Correolide (Koo et al, 1999) and PAP-1 (Schmitz et al, 2005) are novel immunosuppressants which block Kv1.3 channels and are effective in the DTH model. Because the cellular components involved in DTH response are similar to those found in autoimmune diseases and allograft rejection, the results obtained are very promising for the development of Kv1.3 channel blockers as new immunosuppressants.
In the early 1980's a number of compounds were reported to block Kv1.3 channels at micromolar to millimolar concentrations as described by Triggle et al, in “Voltage Gated Ion Channels as Drug Targets” these include classical Kv channel inhibitors such as 4-aminopyridine and tetramethylammonium, and other non specific compounds such as the calcium activated potassium channel blockers quinine and ceteidil, the phenothiazine antipsychotics chloropromazine and trifluoroperazine, the classical calcium channel inhibitors verapamil, diltiazem, nifedipine and nitrendipine, and the beta blocker propranolol.
Also in the 1980's natural products extracted from scorpions, snakes and other marine organisms were found to be potent inhibitors of Kv1.3 channels, these were primarily short peptides (<70 residues) that are stabilised by multiple sulphide bonds. The first of these potent inhibitors was isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus and was named charybdotoxin (ChTX) (Sands et al, 1989), there after screening of other scorpion venoms led to the identification of more potent Kv1.3 blocking toxins, these include margatoxin (MgTX) (Garcia et al, 1993), agitoxin-2 (Garcia et al, 1994), hongotoxin (Koshchak et al, 1998), pandinus imperator toxin 2 (Pi2) (Peter et al, 2001) and orthochirus scrobiculosus (OSK1) (Mouhat et al, 2005) among others. With the exception of OSK1 (300 fold selective over the nearest related channel) none of the scorpion toxins were selective for Kv1.3
One of the most potent and selective Kv1.3 blockers to date, which was extracted from sea anemone is stichodactyla helianthus toxin (Shk) (Pennington et al, 1996) this has been reported for the treatment of autoimmune disease through the blockade of Kv1.3 (U.S. Pat. No. 6,077,680). Shk and its synthetic derivative Shk-Dap22 with improved selectivity profile display pico molar activity (Pennington et al, 1998) however, these peptides proved to have unfavourable properties for further development.
Recently more novel and selective small molecule Kv1.3 channel blockers have been reported for the management of autoimmune disorders. These include the iminodihydroquinolines WIN173173 and CP339818 (Nguyen et al., 1996), the benzhydryl piperidine UK-78,282 (Hanson et al. 1999), correolide (Felix et al., 1999), cyclohexyl-substituted benzamide PAC (U.S. Pat. No. 6,194,458, WO0025774), sulfamidebenzamidoindane (U.S. Pat. No. 6,083,986), Khellinone (Baell et al., 2004), dichloropenylpyrazolopyrimidine (WO-00140231) psoralens (Wulff et al., 1998, Vennekamp et al., 2004, Schmitz et al., 2005) and isoindolines (WO 2008/038051).
Furthermore, the related Kv1.5 channel is expressed in atrial myocytes and is believed to offer therapeutic opportunities for the management of atrial fibrillation for several different reasons (see review of Brendel and Peukert, 2002): (i) There is evidence that Kv1.5 underlies the cardiac ultrarapid delayed rectifier (Kv(ur)) physiological current in humans due to similar biophysical and pharmacological properties (Wang et al., 1993; and Fedida et al., 1993). This has been supported with antisense oligonucleotides to Kv1.5 which have been shown to reduce Kv(ur) amplitude in human atrial myocytes (Feng et al., 1997). (ii) electrophysiological recordings have demonstrated that Kv(ur) is selectively expressed in atrial myocytes, and therefore avoids inducing potentially fatal ventricular arrhythmia through interfering with ventricular repolarisation (Amos et al., 1996; Li et al., 1996; and Nattel, 2002). (iii) Inhibiting Kv(ur) in atrial fibrillation-type human atrial myocytes prolonged the action potential duration compared to normal healthy human atrial myocytes (Courtemanche et al., 1999). (iv) Prolonging the action potential duration by selectively inhibiting Kv1.5 could present safer pharmacological interventions for protecting against atrial re-entrant arrhythmias such as atrial fibrillation and atrial flutter compared to traditional class III antiarrythmics, by prolonging the atrial refractory period while leaving ventricular refractoriness unaltered (Nattel et al., 1999, Knobloch et al., 2002; and Wirth et al., 2003). Class III antiarrythmics have been widely reported as a preferred method for treating cardiac arrhythmias (Colatsky et al., 1990).
Drugs that maintain the sinus rhythm long-term without proarrhythmic or other side effects are highly desirable and not currently available. Traditional and novel class III antiarrythmic potassium channel blockers have been reported to have a mechanism of action by directly modulating Kv1.5 or Kv(ur). The known class III antiarrythmics ambasilide (Feng et al., 1997), quinidine (Wang et al., 1995), clofilium (Malayev et al., 1995) and bertosamil (Godreau et al., 2002) have all been reported as potassium channel blockers of Kv(ur) in human atrial myocytes. The novel benzopyran derivative, NIP-142, blocks Kv1.5 channels, prolongs the atrial refractory period and terminates atrial fibrillation and flutter in in vivo canine models (Matsuda et al., 2001), and S9947 inhibited Kv1.5 stably expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells and Kv(ur) in native rat and human cardiac myocytes (Bachmann et al., 2001). Elsewhere, other novel potassium channel modulators which target Kv1.5 or Kv(ur) have been described for the treatment of cardiac arrhythmias, these include biphenyls (Peukert et al 2003), thiophene carboxylic acid amides (WO0248131), bisaryl derivatives (WO0244137, WO0246162), carbonamide derivatives (WO0100573, WO0125189) anthranillic acid amides (WO2002100825, WO02088073, WO02087568), dihydropyrimidines (WO0140231), cycloalkylamine derivatives (WO2005018635), isoquionolines (WO2005030791), quinolines (WO2005030792), imidazopyrazines (WO205034837), benzopyranols (WO2005037780), isoquinolinones (WO2005046578), cycloakyl derivatives (WO03063797), indane derivatives (WO0146155 WO9804521), tetralin benzocycloheptane derivatives (WO9937607), thiazolidone and metathiazanone derivatives (WO9962891), benzamide derivatives (WO0025774), isoquinoline derivatives (WO0224655), pyridazinone derivatives (WO9818475 WO9818476), chroman derivatives (WO9804542), benzopyran derivatives (WO0121610, WO03000675, WO0121609, WO0125224, WO02064581), benzoxazine derivatives (WO0012492), and the novel compound A1998 purified from Ocean material (Xu & Xu, 2000).
Sulphonamides have been reported to be useful as inhibitors of 11-beta-hydroxysteroid dehydrogenase type1, CCR5, H3 receptor and mitotic kinesins amongst others.
Substituted aryl tertiary sulphonamides, wherein position 4 is substituted with an amide have been claimed as inhibitors of 11-betehydroxysteroid dehydrogenase type1, for the treatment and prevention of hyperglycemia in diseases such as type-2 diabetes (WO2004065351).
Substituted aryl tertiary sulphonamides, wherein position 3 is optionally substituted with substituted alky, alkoxyamino, sulfonyl, acyl, alkoxy carbonyl or aminocarbonyl have been claimed as inhibitors of mitotic kinesins as effective anti cancer agents (WO2007056078).
Substituted 1-3 phenyl sulphonamides bearing a benzyl group and an amido group have been claimed as useful for the treatment and/or prophylaxis of viral diseases, in particular for the treatment of Hepatitis C (WO 2007/110171)
Elsewhere, arylsulophonylaminobenzene derivatives bearing an alkylamino group meta to the sulphonamide were found to be inhibitors of Factor Xa and useful in the treatment of arterial and venous thrombotic occlusive disorders, inflammation, cancer and neurodegenerative diseases (WO 96/40100).
Substituted 1,3 phenylsulphonamides containing an amido group meta to the sulphonamide have been claimed as inhibitors of BACE as an effective means for treating and preventing Alzheimer's and related diseases caused by the production of beta-amyloid (WO 2005/030709).
Substituted 1,3 phenylsulphonamides containing an ether group meta to the sulphonamide have also been claimed as liver X receptor (LXR) modulators useful for the treatment or prevention of diseases associated with the activity of LXR's (WO2003082205)
Substituted 1,3 phenylsulphonamides containing an alkylamino group meta to the sulphonamide have been claimed as amidino protease inhibitors useful for the treatment of protease mediated diseases such as thrombosis, ischemia, or inflammation (WO 1998/01422).
Substituted 1,3 phenylsulphonamides have been claimed as cell proliferation modulators through inhibition of microtubule formation which could be useful for the treatment of cancer related disease (WO00/73264).
Additionally, substituted 1-3 phenylsulphonamides with a substituted amino group meta to the sulphonamide have been claimed as urotensin-II receptor antagonists and CCR-9 antagonists useful for the treatment of gastric diseases, arthritis, osteoperosis and urinary incontinence (WO2004/73634).
It has now surprisingly been found that compounds of general formula (I) set out below act as inhibitors of potassium channels. These compounds are particularly useful for inhibiting the potassium channel Kv1.3 and treating diseases associated with the inhibition of the potassium channel Kv1.3. This invention is not limited to treating diseases mediated by Kv1.3, the compounds also being useful to treat diseases which require Kv1.5 potassium channel inhibition for example atrial fibrillation (Marban, 2002, Brendel and Peukert, 2002).
Thus, in a first aspect, the present invention provides a compound of formula (I)
or its salts or pharmaceutically acceptable derivatives thereof wherein;X1 is selected from a group consisting of CH, O or N;R1 is selected from the group consisting of optionally substituted arylalkyl, and optionally substituted heteroarylalkyl;R2 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl or NR6R7;R3 is selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxy, aryloxy, optionally substituted alkyl, optionally substituted amino, optionally substituted amino sulphonyl or nitrile;R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfamoyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylR5 may be hydrogen or may, together with R4 and X1 (when X1=N), form an optionally substituted saturated or partially saturated 5-7 membered ring with the general formula (II)
Wherein;X2 is C(═O), CH2, CH(R8a) or C(R8a)(R8b);X3 is CH2, CH(R9a), C(R9a)(R9b), NH, N(R9c), O or S;R6 and R7 are the same or different and each represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl;R8a and R8b for each occurrence is independently halogen, optionally substituted amino, optionally substituted amino carbonyl, hydroxyl, optionally substituted acyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl;R9a and R9b for each occurrence is independently halogen, optionally substituted amino, optionally substituted amino carbonyl, hydroxyl, optionally substituted acyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl;R9c is optionally substituted acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl;With the proviso that:When X1 is O then j=0When X1 is N or CH then j=1n=1, 2 or 3
In one embodiment of the invention a compound of the following formula is provided:
or its salts or pharmaceutically acceptable derivatives thereof wherein;X1 is selected from a group consisting of CH, O or N;R1 is selected from the group consisting of optionally substituted arylalkyl, and optionally substituted heteroarylalkyl;R2 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl or NR6R7;R3 is selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxy, aryloxy, optionally substituted alkyl, optionally substituted amino, optionally substituted amino sulphonyl or nitrile;R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfamoyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylR5 may be hydrogen or may, together with R4 and X1 (when X1=N), form an optionally substituted saturated or partially saturated 5-7 membered ring with the general formula (II)
Wherein;X2 is C(═O), C(R8)2;X3 is, C(R9)2, N(R9b), O or S;R6 and R7 are the same or different and each represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl;R8 for each occurrence is independently hydrogen, halogen, optionally substituted amino, optionally substituted amino carbonyl, hydroxyl, optionally substituted acyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl;R9 for each occurrence is independently hydrogen, halogen, optionally substituted amino, optionally substituted amino carbonyl, hydroxyl, optionally substituted acyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl;R9b is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl;With the proviso that:When X1 is O then j=0When X1 is N or CH then j=1n=1, 2 or 3
As used herein, the following definitions shall apply unless otherwise indicated.
The term “optionally substituted” means that a group may be substituted by one or more substituents which may be the same or different. When otherwise not specified, these substituents are selected from alkyl, cycloalkyl, —O—C(halogen)3 preferably —OCF3, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulphonyl, sulphinyl, sulphenyl, sulphonamido or urea.
The term “alkyl group” as used herein, is typically a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, preferably 2, 3, 4, or 5 carbon atoms such as a C1-4 alkyl group or moiety, for example methyl, ethyl, n-propyl, i-propyl, butyl, i-butyl and t-butyl. An alkyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one two or three substituents. Suitable substituents include cyano, halogen, hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulphonamido, nitro, aryl and heteroaryl. The alkyl moiety may also be an “unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety. An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond. An “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
The term “cycloalkyl” as used herein refers to mono- or bicyclic ring or ring systems consisting of 3 to 11 carbon atoms i.e. 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms. The ring system may be a “saturated ring”, which means that the ring does not contain any alkene or alkyne moieties. The cycloalkyl group may also be an “unsaturated ring” which means that it contains at least one alkene or alkyne moiety and the ring system is not aromatic. The cycloalkyl group may be unsubstituted or substituted as defined herein. In addition to the above mentioned substituents one or more ring carbon atoms may also be bonded via a double bond to a group selected from NH, S and O. The cycloalkyl substituent may be bonded via a linker group such as a C1-6 alkyl group, except where the optional substituent is alkyl. One or more hydrogens of the alkyl group in the linker may be replaced by a moiety selected from the group consisting of hydroxy, halo, cyano, amino, thiol, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino and C1-6dialkylamino.
The term “aryl group” as used herein, is typically a C6-10 aryl group such as phenyl or naphthyl. A preferred aryl group is phenyl. An aryl group may be unsubstituted or substituted at any position. Typically, it carries 1, 2, 3 or 4 substituents. Suitable substituents include cyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido, NN-dialkylamino, sulphonamido, aryl and heteroaryl.
The term “carbocyclic” refers to a compound which contains one or more covalently closed ring structures and the atoms forming the backbone of the ring(s) are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings. Carbocyclic groups include both, a “cycloalkyl group”, which means a non-aromatic carbocycle, and a “carbocyclic aryl” group, which means an aromatic carbocycle. The carbocyclic group may optionally be substituted as defined herein.
The term “heterocyclic” or “heterocyclo” as used herein refers to mono- or bicyclic rings or ring systems which include one or more heteroatoms selected from N, S and O. The rings or ring systems include 1 to 6 carbon atoms in addition to the heteroatom(s). The term heterocyclic group include both a “heteroalicyclic” group, which means a non-aromatic heterocycle and a “heteroaryl” group, which means an aromatic heterocycle. The heterocyclic moiety may be unsubstituted or substituted as defined herein and the substituents, when positioned adjacent to one another, may combine to form cycloalkyl or heteroalicyclic ring systems for example methylendioxy or difluoromethylendioxy. The heterocyclic substituent may be bonded via a carbon atom or a heteroatom. The heterocyclic group may also include the oxides of nitrogen and sulfur if nitrogen or sulfur are present in the ring.
The term “heteroaryl” as used herein refers to mono- or bicyclic ring or ring systems which include one or more heteroatoms selected from N, S and O. The rings or ring systems include 1 to 13 carbon atoms in addition to the heteroatom(s) and contain at least one aromatic ring with a heteroatom. The heteroaryl group may also include the oxides of nitrogen and sulfur if nitrogen or sulfur is present. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples of bicyclic heterocycles include but are not limited to indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl and the like. Examples of tricyclic heterocycles include but are not limited to thianthrenyl, xanthenyl, phenoxathiinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl and phenoxazinyl. The heteroaryl group may be unsubstituted or substituted as defined herein. The substituents, when positioned adjacent to one another, may combine to form a cycloalkyl or heteroalicyclic ring for example methylendioxy and difluoromethylendioxy. The heteroaryl substituent may be bonded via a carbon atom or a heteroatom.
The term “arylalkyl”, as used herein, refers to a chemical moiety of formula aryl-C1-6alkyl or C1-6alkyl-aryl as those terms are defined herein.
The term “heteroarylalkyl”, used as herein, refers to a chemical moiety of formula heteroaryl-C1-6alkyl or C1-6alkyl-heteroaryl as those terms are defined herein.
The term “acyl”, as used herein, refers to a chemical moiety of formula (CH2)yC(═O)Rz wherein y is 1-6
The term “amidino” refers to a chemical moiety with the formula (CH2)yC(═NH)NRzR′z wherein y is 1-6.
The term “amido” refers to both, a “C-amido” group which means a chemical moiety with the formula —C(═O)NRzR′z and a “N-amido” group which means a chemical moiety with the formula —NRzC(═O)R′z.
The term “amine” or “amino” refers to a chemical moiety of formula —NRzR′z. The definition of an amine is also understood to include their N-oxides.
A “cyano” group refers to a chemical moiety of formula —CN.
The term “hydroxy” or “hydroxyl” as used herein, refers to a chemical moiety of formula —OH.
The term “halogen” or “halo” refers to an atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
The term “alkanoyl”, as used herein, refers to a chemical moiety with the formula —C(═O)Rz.
The term “sulfone” or “sulfonyl” refers to a chemical moiety with the formula —S(═O)2Rz.
The term “sulfinyl” refers to a chemical moiety with the formula —S(═O)Rz.
The term “sulfenyl” refers to a chemical moiety with the formula —SRz.
A “sulfamoyl” group refers to a chemical moiety with the formula —NRz—S(═O)2NRzR′z.
The term “sulfonamido” refers to both an “S-sulfonamido” group which means a chemical moiety with the formula —S(═O)2NRzR′ z and an “N-sulfonamido” group which means a chemical moiety with the formula —N—S(═O)2R′z.
The term “thiocarbonyl” refers to a chemical moiety with the formula (CH2)yC(═S)Rz wherein y is 1-6.
The term “thio” or “thiol”, as used herein, refers to a chemical moiety of formula —SH.
The term “thioamide” refers to both a “C-thioamido” group which means a chemical moiety with the formula (CH2)yC(═S)NRzR′z and a “N-thioamido” group which means a chemical moiety with the formula (CH2)yNRzC(═S)R′z wherein y is 1-6.
An “urea” group refers to a chemical moiety of formula —NRzC(═O)NRzR′z.
Rz and R′z are independently selected from the group consisting of hydrogen, C1-6alkyl, cycloalkyl, C1-6alkoxy, aryl-C1-6alkyl, aryl and heteroaryl.
One preferred embodiment relates to compounds where R2 is;
NR6R7 or a compound of formula (III), (IV) (V) or (VI)
Wherein;R6 and R7 are the same or different and each represents hydrogen, or optionally substituted C1-3 alkyl;A, Q, T, D, and E are the same or different and each represents C, or N with the proviso that in each instance at least one of A, Q, T, D, or E is N;Where R2 is selected from compounds of formula (III), E may also represent O or S andWhere R2 is selected from compounds of formula (IV), A may also represent O or S;R11 and R12 are the same or different and each represents hydrogen, halogen, hydroxyl, nitrile, optionally substituted amino, optionally substituted acyl, optionally substituted C1-3 alkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring. Preferably, R11 and R12 are alkyl, preferably CH3;R13, R14, R15, R16, and R17 are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, optionally substituted acyl, nitrile, optionally substituted C1-3 alkyl, any of the pairs R13 and R14, or R14 and R15, or R15 and R16, or R16 and R17 or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ringR1 is selected from compounds of Formula (VII)
Wherein;R18, R19, R20, R21 and R22 are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, optionally substituted acyl, nitrile, optionally substituted C1-3 alkyl or optionally substituted alkoxy. Preferably R19, R20 and R21 are the same or different and each represents H, Cl, F, or CH3 most preferably Cl.R23 and R24 are the same or different and each represents hydrogen, hydroxyl, and optionally substituted C1-3 alkyl.R3 is H, F or CH3,Where X1 is O or N:—R4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, substituted benzyl, substituted phenethyl, 3-phenylpropyl, methylpyridine, substituted hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, phenoxyethyl, benzyloxyethyl, acetyl, propionyl, substituted benzoyl, phenacyl, imidazoyl, pyrazoyl, pyridinoyl, acetamide, methylacetamide, dimethylacetamide, ethylacetamide, diethylacetamide, tert-butylacetamide, pyridylacetamide, cyclopropylacetamide, cyclobutylacetamide, cyclopentylacetamide, or cyclohexylacetamide.Where X1 is N, R5 is preferably taken together with X1 and R4 to from an optionally substituted saturated or partially saturated 5-7 membered ring with the general formula (II) as defined above.Preferred compounds are those of formula (VIII);
WhereinX1 is selected from N or O;R2 is NR6R7, substituted imidazole, substituted pyrazole, substituted pyrrole, substituted oxazole, substituted oxadiazole, substituted thiazole, substituted thiadiazole, substituted pyridine, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted triazine, phenyl, fluorophenyl, chlorophenyl, cyanophenyl, aminophenyl, acetamidophenyl, substituted tetrahydrobenzofuran, substituted benzopyran, substituted dihydrobenzodioxin, substituted benzoxazinone, substituted benzooxadiazole, substituted benzodioxole, substituted indoline, substituted indole, substituted indazole or substituted benzomorpholine.R6 and R7 are methylR3, R4, R5, R18, R19, R20, R21 and R22 are as defined above.
More preferred are compounds of formula (IX);
Wherein;X1 is selected from N or O;R2 is NR6R7, substituted imidazole, substituted pyrazole, substituted pyridine, phenyl, fluorophenyl, cyanophenyl, substituted tetrahydrobenzofuran, substituted benzopyran, substituted dihydrobenzodioxin, substituted benzoxazinone, substituted benzooxadiazole, substituted benzodioxole, substituted indoline, or substituted benzomorpholine;R3 is H, or F;When X1 is N or O; R4 is methylpyridine, substituted hydroxyethyl, hydroxypropyl, methylacetamide, dimethylacetamide, ethylacetamide, diethylacetamide, tert-butylacetamide, pyridylacetamide, cyclopropylacetamide, cyclobutylacetamide, cyclopentylacetamide, or cyclohexylacetamide;When X1 is N; X1, R4 and R5 together form substituted piperidine, substituted morpholine, substituted piperazine, substituted pyrrolidine, and substituted imidazolidin-2-one;R6, R7, R19, R20 and R21 are as defined above.Particularly preferred compounds of the invention include:    N-[3-(Benzenesulfonyl-benzyl-amino)-phenyl]-acetamide    3-Methyl-3H-imidazole-4-carboxylic acid [3-(benzenesulfonyl-benzyl-amino)-phenyl]-amide    1-Methyl-1H-imidazole-4-carboxylic acid [3-(benzenesulfonyl-benzyl-amino)-phenyl]-amide    N-[3-(Benzenesulfonyl-benzyl-amino)-phenyl]-2-phenyl-acetamide    N-[3-(Benzenesulfonyl-benzyl-amino)-phenyl]-2-methoxy-acetamide    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[3-(4-phenyl-piperazin-1-yl)-phenyl]-amide    N-Benzyl-N-[3-(3-phenyl-piperazin-1-yl)-phenyl]-benzenesulfonamide    N-Benzyl-N-[3-(4-phenyl-piperazin-1-yl)-phenyl]-benzenesulfonamide    N-Benzyl-N-(3-morpholin-4-yl-phenyl)-benzenesulfonamide    Pyridine-3-sulfonic acid benzyl-[3-(4-phenyl-piperazin-1-yl)-phenyl]-amide    3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide    4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide    1,2-Dimethyl-1H-imidazole-4-sulfonic acid benzyl-(3-morpholin-4-yl-phenyl)-amide    N-Benzyl-3-cyano-N-(3-morpholin-4-yl-phenyl)-benzenesulfonamide    4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid benzyl-(3-morpholin-4-yl-phenyl)-amide    N-Benzyl-3-cyano-N-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-benzenesulfonamide    N-Benzyl-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide    1-Methyl-1H-pyrazole-4-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide    1,2-Dimethyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide    2-Methyl-2H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide    4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide    1-Methyl-1H-pyrazole-4-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide    3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide    N-(4-Chloro-benzyl)-3-cyano-N-(3-morpholin-4-yl-phenyl)-benzenesulfonamide    2-Methyl-2H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide    4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide    1-Methyl-1H-pyrazole-4-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide    3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide    Pyridine-3-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide    1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide    1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[4-fluoro-3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide    1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide    1-Methyl-1H-pyrazole-3-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide    1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide    1-Methyl-1H-pyrazole-3-sulfonic acid benzyl-(3-morpholin-4-yl-phenyl)-amide    1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide    1-Methyl-1H-pyrazole-3-sulfonic acid benzyl-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide    N-Benzyl-3-cyano-4-fluoro-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide    2-Methyl-2H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide    1-Methyl-1H-pyrazole-4-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide    N-(4-Chloro-benzyl)-3-cyano-4-fluoro-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide    N-(4-Chloro-benzyl)-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide    Pyridine-3-sulfonic acid benzyl-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-a(2-oxo-imidazolidin-1-yl)-phenyl]-amide    Pyridine-3-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-ylbenzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide
As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, araalkyl amines or heterocyclic amines.
The compounds of the invention can contain one or more chiral centres. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all stereo isomers of the compounds shown, including racemic and non racemic mixtures and pure enantiomers and/or diastereoisomers.
As discussed herein, the compounds of the invention are useful in the treatment of various conditions. Thus, in a second aspect, the present invention provides a compound of formula (I) as defined herein for use in medicine. Preferably the compound is used to prevent or treat conditions which require inhibition of potassium channels, such as immunological disorders, including psoriasis, rheumatoid arthritis and multiple sclerosis.
A further aspect the present invention provides a pharmaceutical formulation comprising at least one compound of formula (I) or as defined herein and optionally one or more excipients, carriers or diluents.
The compositions of the invention may be presented in unit dose forms containing a predetermined amount of each active ingredient per dose. Such a unit may be adapted to provide 5-100 mg/day of the compound, preferably either 5-15 mg/day, 10-30 mg/day, 25-50 mg/day 40-80 mg/day or 60-100 mg/day. For compounds of formula I, doses in the range 100-1000 mg/day are provided, preferably either 100-400 mg/day, 300-600 mg/day or 500-1000 mg/day. Such doses can be provided in a single dose or as a number of discrete doses. The ultimate dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be at the doctor's discretion.
The compositions of the invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For applications to the eye or other external tissues, for example the mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.
Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
The compositions of the invention can be used to treat conditions which require inhibition of potassium channels, for example in the treatment of immunological disorders. Thus, in further aspects, the present invention provides:
(i) A method of treating or preventing a disorder which requires potassium channel inhibition, eg immunological disorders comprising administering to a subject an effective amount of at least one compound of the invention or a pharmaceutical composition of the inventionand(ii) the use of a compound of the invention in the manufacture of a medicament for use in potassium channel inhibition.
In particular, the medicament is for use in the treatment or prevention of psoriasis, rheumatoid arthritis, multiple sclerosis and other immunological disorders and arrhythmia.
Preferred embodiments of the first aspect apply to all other aspects mutatis mutandis.
The compounds of formula (I) may be prepared by conventional routes, for example those set out in Schemes 1 to 6 shown below.
Compounds of formula (I) where X1 is N and R4 and R5 are described as in claim 1, may be synthesised by reaction of an amine of formula NR4R5 with an aromatic halide of formula (X) where G is Cl, Br, I or F as shown in Scheme 1. This substitution may be carried out thermally, optionally with microwave heating and optionally in the presence of solvent. Alternatively, the substitution may be carried out via an organometallic mediated coupling between an amine of formula NR4R5 with an aromatic halide of formula (X). Suitable conditions include those developed by Buchwald et al1. The Buchwald coupling may be carried-out using a palladium-organophosphine complex, such as that derived from palladium acetate and dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl in solvent such as dioxane, and in the presence of a base such as sodium tert-butoxide. The reaction may be carried out at room temperature or optionally with heating or optionally with microwave heating.
Compounds of formula (X) may be prepared from compounds of formula (XI) and sulphonyl chlorides of formula R2SO2Cl in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature. Compounds of formula R2SO2Cl are either commercially available or may be prepared by standard published methods known to those skilled in the art.
Compounds of formula (XI) may be prepared from compounds of formula (XII) via reductive amination of a ketone or aldehyde of formula R1(═O). The reaction may be performed in a one pot procedure with in situ formation and reduction of the imine or via a two stage process where the imine is isolated and purified prior to reduction. Imine formation is performed under acid catalysis, suitable catalysts include acetic acid. Reduction may be performed using standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature with a suitable reductant such as sodium triacetoxyborohydride or sodium cyanoborohydride, the reduction may also be performed using catalytic hydrogenation. Compounds of formula (XII) are either commercially available or may be prepared by standard published methods familiar to those skilled in the art.

Compounds of formula (I) where X1 is N, R5 is H and R4 is optionally substituted acyl may be synthesised by reaction of compounds of formula (XIII) and compounds of formula RzCOA where A is OH, Cl or Br as shown in Scheme 2. Where A is OH, the reaction may be carried out in the presence of a coupling reagent such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) or 2-(7-aza-1H-benztriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) utilising standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at range of temperatures from ambient to reflux temperature or optionally with microwave heating. Where A is Cl or Br the reaction may be carried out in the presence of base such as pyridine, or diisopropylamine and in the presence of solvent such as dichloromethane or tetrahydrofuran, optionally at room temperature or optionally with heating or optionally with microwave heating. Compounds of formula RzCOA are either commercially available or may be prepared by standard published methods familiar to those skilled in the art.
Compounds of formula (I) where X1 is N, R5 is H and R4 is optionally substituted sulfonyl may be synthesised by reaction of compounds of formula (XIII) and compounds of formula RZSO2Cl. The reaction may be carried out in the presence of base such as pyridine, or diisopropylamine and in the presence of solvent such as dichloromethane or tetrahydrofuran, optionally at room temperature or optionally with heating or optionally with microwave heating.
Compounds of formula (XIII) may be prepared from compounds of formula (XIV) by removal of a protecting group (P) in a preferred instance a tertbutylcarboxy (BOC) group. This may be done using standard methods of acidic or basic hydrolysis or via protolytic decomposition such as trifluoroacetic acid in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature.
Compounds of formula (XIV) may be prepared from compounds of formula (XV) and sulphonyl chlorides of formula R2SO2Cl in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature. Compounds of formula R2SO2Cl are either commercially available or may be prepared by standard published methods known to those skilled in the art.
Compounds of formula (XV) may be prepared from compounds of formula (XVI) via reductive amination of a ketone or aldehyde of formula R1(═O). The reaction may be performed in a one pot procedure with in situ formation and reduction of the imine or via a two stage process where the imine is isolated and purified prior to reduction. Imine formation is performed under acid catalysis, suitable catalysts include acetic acid. Reduction may be performed using standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature with a suitable reductant such as sodium triacetoxyborohydride or sodium cyanoborohydride, the reduction may also be performed using catalytic hydrogenation. Compounds of formula (XVI) are either commercially available or may be prepared by standard published methods known to those skilled in the art.
Alternatively, compounds of formula (I) where X1 is N and R4 and R5 are described as in claim 1, may be prepared from compounds of formula (XVII) and sulphonyl chlorides of formula R2SO2Cl as shown in Scheme 3. Typically, the reaction is performed in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature. Compounds of formula R2SO2Cl are either commercially available or may be prepared by standard published methods known to those skilled in the art.
Compounds of formula (XVII) may be prepared from compounds of formula (XVIII) via reductive amination of a ketone or aldehyde of formula R1(═O). The reaction may be performed in a one pot procedure with in situ formation and reduction of the imine or via a two stage process where the imine is isolated and purified prior to reduction. Imine formation is performed under acid catalysis, suitable catalysts include acetic acid. Reduction may be performed using standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature with a suitable reductant such as Sodium triacetoxyborohydride or sodium cyanoborohydride, the reduction may also be performed using catalytic hydrogenation. Compounds of formula (XVIII) where R5 is H are either commercially available or may be prepared by standard published methods known to those skilled in the art.
Compounds of formula (XVIII) where R4 and R5 are taken together to form an optionally substituted saturated or partially saturated 5 membered ring may be synthesized from compounds of formula (XIX) via reduction of a nitro group as shown in Scheme 4. This reduction may be accomplished via a suitable reducing agent such as Tin (II) chloride in the presence of hydrochloric acid or via catalytic hydrogenation using a suitable catalyst such as palladium on carbon which may be carried out at atmospheric or elevated pressure and optionally with microwave heating and optionally in the presence of a hydrogen equivalent such as ammonium formate.
Compounds of formula (XIX) may be prepared via cyclisation of compounds of formula (XX) where Q1 is CH2Cl, CH2Br, CO2H or C(O)Cl. This cyclisation may be accomplished in the presence of base such as pyridine or sodium hydride and in the presence of solvent such as dichloromethane or tetrahydrofuran. The cyclisation may be carried out at room temperature or optionally with heating or optionally with microwave heating.
Compounds of formula (XX) may be synthesized via reaction of compounds of formula (XXI) and compounds of formula (XXII) where Q2 is CO2H, C(O)Cl, CH2Cl, or CH2Br, or X2 and Q2 taken together are an isocyanate group.
Compounds of formula (XXI) and (XXII) are either commercially available or may be prepared by standard published methods known to those skilled in the art.
Alternatively, compounds of formula (XVII) where R4 and R5 are taken together to form an optionally substituted saturated or partially saturated 5 membered ring may be prepared from compounds of formula (XXIII) by removal of a protecting group (P) as shown in Scheme 5. In a preferred instance a tertiarybutylcarboxy (BOC) group is used. This may be done using standard methods of acidic or basic hydrolysis or via protolytic decomposition such as trifluoroacetic acid in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature.
Compounds of formula (XXIII) may be prepared via cyclisation of compounds of formula (XXIV) where Q1 is CO2H, C(O)Cl, CH2Cl, or CH2Br. This cyclisation may be accomplished in the presence of base such as pyridine or sodium hydride and in the presence of solvent such as dichloromethane or tetrahydrofuran. The cyclisation may be carried out at room temperature or optionally with heating or optionally with microwave heating.
Compounds of formula (XXIV) may be synthesized via reaction of compounds of formula (XXII) and compounds of formula (XXV) where Q2 is CO2H, C(O)Cl, CH2Cl, or CH2Br, or X2 and Q2 taken together are an isocyanate group. This reaction may be accomplished in the presence of base such as pyridine or sodium hydride and in the presence of solvent such as dichloromethane or tetrahydrofuran. The cyclisation may be carried out at room temperature or optionally with heating or optionally with microwave heating. Compounds of formula (XXII) or (XXV) are either commercially available or may be prepared by standard published methods known to those skilled in the art.
Compounds of formula (I) where X1 is O and R1, R2 and R4 are as described in the claims may be prepared from phenols of formula (XXVI) and compounds of formula R4Br by standard methods such as alkylation as shown in Scheme 6. Typically this reaction is performed in the presence of a base for example potassium carbonate utilising standard methods familiar to those skilled in the art such as reaction in solvent such as dimethylformamide, tetrahydrofuran, acetonitrile or dichloromethane at a range of temperatures from ambient to reflux temperature. Alternatively, compounds of formula (I) where X1 is O and R4 are described in the claims may be prepared from phenols of formula (XXVI) and compounds of formula R4OH by standard methods such as alkylation for example; Mitsunobu coupling (Mitsunobu 1981). The Mitsunobu coupling may be carried-out using diisopropyl azodicarboxylate (DIAD) or other appropriate coupling agents in the presence of triphenylphosphine. Typically, the reaction may be carried out at room temperature or optionally with heating or optionally with microwave heating in a suitable solvent for example tetrahydrofuran, acetonitrile or dichloromethane.
Compounds of formula (XXVI) may be prepared from compounds of formula (XXVII) and sulphonyl chlorides of formula R2SO2Cl in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature. Compounds of formula R2SO2Cl are either commercially available or may be prepared by standard published methods known to those skilled in the art.
Compounds of formula (XXVII) may be prepared by de-protection of phenols with the general formula (XXVIII) where P is a protecting group, for example methyl. Typically, the de-methylation is carried out using halo borides for example Boron tribromide in a suitable solvent such as dichloromethane, tetrahydrofuran at temperatures ranging from 0° C. to reflux.
Compounds of formula (XXVIII) may be prepared from compounds of formula (XXIX) via reductive amination of a ketone or aldehyde of formula R1(═O). The reaction may be performed in a one pot procedure with in situ formation and reduction of the imine or via a two stage process where the imine is isolated and purified prior to reduction. Imine formation is performed under acid catalysis, suitable catalysts include acetic acid. The reduction may be performed using standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature with a suitable reductant such as sodium triacetoxyborohydride or sodium cyanoborohydride, the reduction may also be performed using catalytic hydrogenation. Compounds of formula (XXIX) are either commercially available or may be prepared by standard published methods known to those skilled in the art.
The compounds of the invention are found to be inhibitors of potassium channels (Kv) and are therefore therapeutically useful. Such compounds are believed to be novel and the present invention also provides for these compounds. The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds.
Many of the starting materials referred to in the reactions described above are available from commercial sources or can be made by methods cited in the literature references.